Metformin modulate immune fitness in hepatocellular carcinoma: Molecular and cellular approach
Abstract
Hyperinsulinemia, hyperglycemia, and chronic inflammation may play a role in hepatocellular carcinoma (HCC). Treatment of HCC patients with the antidiabetic medication metformin corrected the pathological changes of HCC by affecting proliferation, apoptosis, and angiogenesis. On the other hand, our review aims to uncover new pathways underlying metformin's anti-tumor action in the liver, focusing on immunological mediators and immune archetypes. In this review, we discuss the effect of metformin on restructuring the HCC immune microenvironment, such as dendritic cells, T cells, Tregs, macrophages, neutrophils, and myeloid-derived suppressors cells (MDSCs). Furthermore, Metformin also changes the expression pattern of immune mediators in HCC immune microenvironment, including programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), transforming growth factor-beta (TGF-β), Interleukin 12 (IL-12), indoleamine 2,3 dioxygenase (IDO), forkhead box protein P3 (FOXP3), and interferon-gamma (IFN-γ). This review summarizes a state-of-the-art understanding of the molecular mechanisms underlining novel anticarcinogenic approaches of metformin through modulation of liver cancer immune microenvironment both on the cellular and molecular scales, which aids in regaining immune fitness and thus better prognosis. The changes in tumor immune architecture and mediators induced by metformin make it a robust antineoplastic agent with multiple mechanisms of action, especially for…
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